17-alkyl-20-keto substituted pregnenes, pregnadienes and methods of preparing the same



United States Patent l 3,351,639 17-ALKYL-20-KETO SUBSTITUTED PREGNENES,

PREGNADIENES AND METHODS OF PREPAR- ING THE SAME George Rodger Allen,In, Old Tappan, and Martin Joseph Weiss, Oradell, N.J., assignors toAmerican Cyanamid Company, Stamford, Conn., a corporation of Maine NoDrawing. Filed Mar. 20, 1963, Ser. No. 266,491 2 Claims. (Cl. 260-3973)This invention relates to new organic compounds. More particularly, itrelates to 17-alkylated pregnenes, pregnadienes and methods of preparingthe same.

The new steroids of the present invention may be illustrated by thefollowing formula:

wherein R is an alkyl radical; R is selected from the group consistingof hydrogen, hydroxyl, halogen and alkanoyloxy radicals; R is selectedfrom the group consisting of hydrogen, lower alkyl and chlorine; and:

| R1 C4 (CBRB) is a radical selected from the group consisting of:

then R is selected from the group consisting of hydrogen 3,351,639Patented Nov. 7, 1967 and halogen and when:

then R is hydrogen.

Also included within the purview of the present invention are17a-alkyl3-alkoxy-6-hydrogen or lower alkylpregna-S-en-ZO-ones which aredescribed in the examples hereinafter.

The present compounds are, in general, white crystalline solids. Theyare substantially insoluble in water and somewhat soluble in the usualorganic solvents such as benzene, petroleum ether and the like.

A number of compounds of this invention can be prepared by treatment ofthe corresponding A -3fi-ols (I) with appropriate reagents. Thus,treatment with [i-chloroa,a,fi-trifluoroethyldiethylamine produces the3,8-fluoroderivatives (II), treatment with thionyl chloride gives the3B-chloro derivatives (III), and treatment with potassium t-butoxide andan alkyl halide furnishes the 3,8- alkoxy derivatives (IV). TheB-unsubstituted methylene derivatives can be obtained by treatment ofthe corresponding A -3 3-chloro (V) derivative with sodium and analcohol such as amyl alcohol, a procedure which also usually reduces theZO-keto group to a 20-01. The desired ZO-ketone (VI) is then obtained byoxidation of the 20-01. The A derivatives can be prepared by reductionof the corresponding A -3-ketone (VII), preferably with a metal hydrideto the A -3B-ol (VIII), which with acetic acid undergoes dehydrationwith the formation of the A -diene (IX). When lithium aluminum hydrideis utilized as the reducing agent, the ZO-keto group also undergoesreduction and it is necessary to oxidize, after formation of the3,5-diene, to a ZO-ketone (XI). With metal hydrides, such as sodiumborohydride, in the presence of an alcoholic solvent, such as methanol,as the reducing agent preferential reduction of the 3-ketone can beachieved and an oxidation step is not necessary. Thus, use of the latterreagent also affords the A -3fl-ol-20- ketones (X). Similar treatment ofa A -3-ketone will produce the M' -3 601 (XIII). This novel method forthe preferential reduction of a 3-carbon1yl group in a 17-alkylpregnl-ene (or 4,6-diene)-3,20-dione to give the corresponding A orA -3,8-ol is to be considered part of this invention. Reaction of the A-3B-ols or the A 3/3-ols with alkanoylating agents will furnish thecorresponding Bfi-alkanoyloxy derivatives. These reactions areillustrated by the following equations, and more specifically, by theexamples which follow.

F- \p t no I O:

XIII NaBH l CHgOH l il 1 HO-- I XIV The compounds of the presentinvention possess progestational activity and are useful in place ofknown progestational steriods, such as progesterone, in the treatment,for example, of habitual abortion. These compounds have an additionalutility in that they are effective when administered by the oral route.Furthermore, these compounds are also useful by oral administration forthe inhibition of conception.

The following examples illustrate in detail the preparation of thecompounds of the present invention.

Example 1 .--Preparatiorz 0 f 1 7 u-ethy l-3 ,B-fluoropregn-S en-ZO-one(II) A solution of 340 mg. (1 mmole) of 17ot-ethylpregnenolone[Tetrahedron Letters, [11], 489 (1962)] and 200 mg. (1.06 mmoles) of,B-chloro-a,a,fi-trifluoroethyl diethylamine in 10 ml. of methylenechloride is allowed to stand in the refrigerator 17.5 hours. Thesolution is diluted with methylene chloride, washed with sodiumcarbonate solution and water, dried over magnesium sulfate andevaporated. Crystallization of the residue from methanol gives whitecrystals, melting point 178- 180 C.; [ch 64 (c. 0.69, chloroform);

A533; 5.91; Example 2.Prepamti0n of 3 3-flu0ro-17u-methylpregn--en-20-0ne (II) Treatment of 146 mg. (0.44 mmole) of17amethylpregnenolone [Helv. Chim. Acta, 32, 270 (1949)] with 94 mg.(0.5 mmole) of fl-chloro-a,u,fl-trifiuoroethyldiethylamine in ml. ofmethylene chloride as described in Example 1 gives, afterrecrystallization from dilute methanol, white crystals, melting point129131 C.; [a1 57.5 (c. 1.1, chloroform);

methylpregn-5-en-20-0ne (II In the manner described in Example 1, 500mg. of 17a-ethyl-6-methylpregnenolone [Chemistry and Industry, 118(1963)] is treated with 300 mg. offi-chloro-a,a,fltrifiuoroethyldiethylamine. The product ischromatographed on silica gel, and the solids eluted by benzene XII arerecrystallized from dilute methanol to give white crystals, meltingpoint 127 C.; [ch -73 (c. 1.1, chloroform) max.

Example 4.Preparati0n 09 3acet0xy17a-0ctylpregna- 3,5-dien-20-0=ne Asolution of 2.00 g. of 17a-octylprogesterone [Chemistry and Industry,118 (1963)] in 30 m1. of acetic anhydride and 30 ml. of acetyl chlorideis heated on the steam bath for 2 hours. The resulting solution ischilled in ice and poured with stirring onto cracked ice. After theexcess reagents hydrolyze, the mixture is extracted with methylenechloride. The extract is washed repeatedly with water, dried overmagnesium sulfate and the solvent removed. The residue has m2 235 m((218,000) and KBr max.

Example 5.-Preparati0n of 17ot-0ctylpiregnen0l0ne (I) A solution of 2.00g. of 3-acetoxy-l7w-octylpregna-3,5- dien-20-one (Example 4) and 2.00 g.of sodium borohydride in 125 ml. of methanol and 60 ml. oftetrahydrofuran containing 5 ml. of water is kept at room temperaturefor 18 hours. The solution is diluted with Water and extracted withmethylene chloride. The organic solution is dried over magnesiumsulfate, and the solvent is evaporated to give material which has noappreciable ultraviolet absorption at 20 7/ ml. and has Treatment of17a-octylpregnenolone (Example 5) with ,fl-chloro-a,oz,B-trifiuoroethyldiethylamine in the manner of Example 1 produces3fl-fiuoro-17a-octylpregn-5-en-20- one.

7 Example 7.-Preparatin of 3,8-chl0r0-17a-e2thylpregn-5- en-ZO-one (III)Example 8.Preparati0n of SB-chloro-I 7a-0ctylpregn-5- en-ZO-one (111)When l7a-octylpregnenolone (Example is reacted with thionyl chloride inthe manner of Example 7, the product 3fl-chloro-17a-octylpregn-5-en-20-one is obtained.

Example 9.-Preparati0n of 17a-ethyl-3B-meth0xy-6-mefhylpregn-5-en-20-0ne (IV) To a solution obtained by the interactionof 59 mg. of potassium with 20 ml. of t-butyl alcohol is added 358 mg.of 17a-ethyl-6-methylpregnenolone, 15 ml. of t-butyl alcohol being usedto aid in the transfer. The solution is heated at reflux temperaturewith mechanical stirring and a solution of 5 ml. of methyl iodide in 20ml. of t-butyl alcohol is added dropwise over 2 hours. Heating andstirring are continued for an additional 2 hours. The cooled mixture isdistributed between Water and methylene chloride. The organic solutionis washed with saline,

dried over magnesium sulfate and evaporated. The residue ischromatographed on silica gel. The material eluted by the first 125 ml.of a benzene-ether (99:1) solution is recrystallized from dilutemethanol to give White needles, melting point 162l64 C.;

Example 10.Preparation of I 7m-ethyl-3/3-0ctyl0xypregn- 5-en-20-one (IV)Treatment of 17u-ethylpregnenolone with potassium t-butoxide and octyliodide as described in Example 9 produces17a-ethyl-3,B-octyloxypregn-Sen-20-one.

Example I1.Preparati0n of 3fl-eth0xy-I7a-00tylpregn- 5-en-20-0ne (IV)When 17a-0ctylpregnenolone is reacted with potassium t-butoxide andethyl iodide in the manner of Example 9 the product3p-ethoxy-17a-octylpregn-5-en-20-one is obtained.

Example 12.Preparati0n of I7a-ethyl-3/3,20-dihydr0xypregn-4-ene (VIII) Amixture of 692 mg. of 17a-ethylprogesterone [Chemistry and Industry, 118(1963)] and 130 mg. of lithium aluminum hydride in 30 ml. of ether isheated at reflux temperature for 30 minutes with magnetic stirring.Ethyl acetate is added slowly, followed by water. The organic solutionis dried over magnesium sulfate and evaporated to give a solid which hasno appreciable ultraviolet absorption and no absorption in the carbonylregion of its infrared spectrum.

Example 13.Preparation of I7a-ethyl-3/3-hydr0xypregn-4-en-20-one (X) Asolution of 500 mg. of l7a-ethylprogesterone and 500 mg. of sodiumborohydride in 25 ml. of methanol, 15 ml. of tetrahydrofuran and 1 ml.of water is kept at room temperature for 21 hours. The solution isdistributed between water and methylene chloride. The organic solutionis dried over magnesium sulfate and evaporated to give a solid residuewhich is absorbed onto silica gel.

The solid contained in the benzene-ether (:5) eluates is recrystallizedfrom acetone-hexane to furnish white plates, melting point 179l8l C.;[111 +43 (c. 1.48, chloroform); no appreciable ultraviolet absorption at20 /ml.;

max.

Example I4.Preparati0n of 3B-hydr0xy-17a-0ctylpregn-4-en-20-one (X)Treatment of 17a-octylprogesterone with sodium borohydride in the mannerof Example 13 gives the product 3fl-hydroxy-17a-octylpregn-4-en-ZO-one.

Example 15.-Preparati0n 0) I7a-ethyl-20-hydr0xypregna-3,5-diene (IX)MoOH m.

228, 234, 242 mp and x53; 3.0a

Example 16.Preparati0n of 17a-ethylpregna-3,5- diene-ZO-one (XI) To anice-chilled slurry of 700 mg. of chromium trioxide in 10 ml. of pyridineis added a solution of 17aethyl-20g-hydroxypregna-3,5-diene (Example 15)in 15 ml. of pyridine. The mixture is then magnetically stirred for 30minutes and then kept at room temperature for 22 hours. The mixture ispoured into water and extracted with methylene chloride. Filtration isnecessary to remove some undissolved solid. The organic solution isdried over magnesium sulfate and evaporated. The residue is extractedwith hot benzene and the extract is adsorbed onto silica gel. The columnis washed with benzene and the solid remaining on evaporation of thesolvent is recrystallized from dilute methanol to give white crystals,melting point 155157 C.;

228, 234, 248 m, and W max.

Example I 7.Preparati0n of I 7 ot-ethylpregna-3 ,5 dien-ZO-one (XI) Asolution of 17a-ethyl-3fl-hydroxypregn-4-en-20-one (Example 13) in ml.of 50% acetic acid is heated at reflux temperature for 45 minutes. After10 minutes a solid separates from the solution. The mixture is chilledand filtered to give 360 mg. of white crystals, melting point -458 C.This material is recrystallized from methanol to give white needles,melting point 155l57 C. The identity of this material with that ofExample 16 is shown by melting point and infrared and ultravioletspectral comparisons.

Example I8.Preparali0n of I 7ot-0ctylpregna-3,5- dien-ZO-one (XI)Treatment of 3B -hydroxy-l7a-octylpregn-4-en-20-one (Example 14) withacetic acid as described in Example 17 produces17a-octylpregna-3,5-dien-20-one.

Example I9. Preparation of 3fl-acet0xy-17a-ethylpregn-4-en-20-0ne (XII)Treatment of 3B hydroxy-17a-octylpregn-4-en-20-one (Example 14) withacetic anhydride by the procedure of Example 19 gives3,8-acetoxy-17a-octylpregn-4-en-20-one.

When 17a-ethyl-6a-methylprogesterone [Chemistry and Industry, 118(1963)] is reacted with sodium borohydride by the procedure described inExample 13 the product 17oz ethyl-3 8-hydroxy-6a-methylpregn-4-en-20-one is obtained.

Example 23.Preparatin of 3fl-acet0xy-I7ot-ethyl6amethylpregn-4-en-20-0ne(XII) Treatment of 17ot-ethyl-3fi-hydroxy-6ix-methylpregn-4- en-20-one(Example 22) with acetic anhydride in the manner of Example 19 isproductive of 3p-acetoxy-17aethyl-6wmethylpregn-4-en-20-one.

Example 24 .Preparation of 1 7oc-etl2yl-6-mellzylpregna-3 ,5-dien-20-0ne (XI) When 17oz ethyl-3,8-hydroxy-6ot-methylpregn-4-en-20-one (Example 22) is treated with acetic acid in water according to theprocedure described in Example 17, the product is17a-ethy]-6-methylpregna-3,5-dien-20-one.

Example 25.Preparatian of I 7at-ethyl-3 8-hydroxypregna-4,6-dien-20-0ne(XIV) A solution of 400 mg. of 17rx-ethylpregna-4,6-diene- 3,20-dione[Chemistry and Industry, 118 (1963)] in 150 ml. of methanol, 10 ml. oftetrahydrofuran and 2 ml. of water is treated with 400 mg. of sodiumborohydride and kept at room temperature for hours. Most of the solventis removed and the concentrate is distributed between water andmethylene chloride. The organic phase is dried over magnesium sulfateand evaporated. The residue is recrystallized from methanol to givewhite needles, melting point 198205 C.;

McOI-I 2 2 23 247 2.80, 5.95, 6.10, 6.2071

Example 26.-Preparation 0f 3fi-aceloxy-I 70t-Llllylpregna-4,6-clien--one(XV) Treatment of 60 mg. of 17a-ethyl-3fl-hydroxypregna 4,6-dien-20-one(Example with 1 ml. of acetic anhydride in 10 ml. of pyridine in themanner described in Example 19 produces White crystals. This solid isrecrystallized from dilute methanol to give white crystals, meltingpoint 176-178 C.;

Example 27.Preparazz'on 0f l7u-ethyl-6-methylpi egna-4,6-dien-3,20-di0ne(XIII) AKBr max.

max.

10 The extracts are washed successively with water, 1% sodium hydroxidesolution and finally with saline. Removal of the solvent gives a residuewhich crystallizes from acetone-hexane to give White needles, meltingpoint 182-183 C.; +51 (c. 0.97, chloroform);

290 H1,u (623,600); AH; 5.91, 6.00, 6.15, 6.30

Example Z8.Preparali0n 0] I7u-etl1yl'3,B-hydr0xy- 6-mtlzylpregna-4,6-dien-20-0ne (XIV) Treatment of17a-ethyl-6methylpregna-4,6-diene-3,20- dione (Example 27) with sodiumborohydride in the manner of Example 25 is productive of17u-ethyl-3fl-hydroxy- 6-methylpregua-4,6-dien-20-one.

Example 29.-Preparalion 09 I 7 a-eth yl-6 -metlzy l-3fi-0ctan0yl0xypregna-4,6-dien-2 0-0ne (XV) Treatment of17ot-ethyl-3[3-hydroxy G-methylpregna- 4,6-dien-20-one with caprylicanhydride in pyridine solution in the manner described in Example 19gives 17aethyl-6-methyl-3B-octanoyloxypregna-4,6-dien-20-one.

Example 30.- Preparati0n 0 I7ot-0ctylpregna- 4,6-diene-3,20-di0ne (XIII)Treatment of 17a-octylprogesterone [Chemistry and Industry, 118 (1963)]in dioxane saturated with hydrogen chloride withdichlorodicyano-p-benzoquinone in the manner described in Example 27gives 17a-octylpregna- 4,6-diene-3,20-dione.

Example 31.-Preparati0n of 3fl-hyd'r0xy-I7a-octylpregna ,6-dien-20-one(XIX) Treatment of 17ot-octylpregna 4,6-diene 3,20-dione (Example 30)with sodium borohydride according to the procedure of Example 25furnishes 3B-h ydroxy-17ot-octylpregna-4,6-dien-20-one.

Example 32.Preparati0n of 3/3-acel0xy-I7ot-0ctylpregna-4,6-a ien-20-ane(XV) Treatment of 3p-hydroxy-17ot-octylpregna-4,6-dien-20- one (Example31) with acetic anhydride in pyridine in the manner of Example 19furnishes 3fi-acetoxy-l7aoctylpregna-4,6-dien-20-one.

Example 33.Preparation of 6:1,706-6POW-1 7a-etlzylpregn-4-ene-3,20-dioneA solution of 2 g. of 17ot-ethylpregna-4, 6-diene-3,20- dione, 260 ml.of methylene chloride and a solution of 6.43 g. of monoperphthalic acidin 134 ml. of ether is kept at room temperature, protected frommoisture, for 72 hours. The resulting phthalic acid is removed byfiltration. The filtrate then is diluted with 300 ml. of methylenechloride, washed with saturated sodium carbonate solution, saline andthen with water, dried with anhydrous magnesium sulfate and evaporatedto dryness. Trituration with. ether followed by filtration gives 81% mg.(40%) of product, melting point 218-222 C. Two recrystallizations frommethylene chloride-ether gives white crystals, melting point 226-230 C.[111 +49 (0.99% in CHCl A3152 21-1 m (614,650); Ail; 5.86, 5.95. 6.11

Example 34.-Preparati0n 0f 17a-0ctylpregna- 4,6-diene-3,20-di0neTreatment of 17a-0ctylprogesterone (7.7 g.) with 2,3-dichloro-5,6-dicyano-p-benzoquinone in the manner described in Example27 is productive of crude 17ot-octylpregna-4,6 -diene-3,20-dione (7.74g.) which is subjected to partition chromatography on diatomaceousearth. The system heptanezZ-methoxy ethanol is used; the column ispacked with 750 g. of diatomaceous earth. The first 950 ml. of eflluentcontains a negligible amount of material; the next 950 ml. of efiluentcontains the major peak which on evaporation gives 2.5 g. of product;[111 (0.40% in CHCl max. 283 mp. (619,500); Affif; 5.88, 5.98, 6.17,6.3;; Example 35.Preparation of6a.,7tx-ep0xy-17a-0ctylpregn-4-ene-3,20-di0ne max. Example36.-Preparati0n of 6-chI0r0-17a-ethylpregna-4,6-diene-3,20-dione Asolution of 30 ml. of glacial acetic acid saturated at room temperaturewith hydrogen chloride is added 500 mg. of 6a,7a-epoxy-17a+ethylpregn4-ene-3,20-dione (Example 33). After standing for four hours, thesolution is poured onto 60 ml. of iced water and stirred for minutes.The amorphous material is collected by filtration and recrystallizedfrom ether-petroleum ether to give 203 mg. (39%) of product, meltingpoint 157160 C. Recrystallization from methylene chloride-ether giveswhite crystals, melting point 166170 C., [aJ +28 (0.78% in CHCl W 285 mp(618,200); x55; 5.89, 6.02, 6.24, 6.31,.

Example 37.Preparati0n of 6-chl0r0-17a-0ctylpregna-4,6-diene-3,20-di0neA333 284 my. (627,600); x219 5.91, 6.02, 6.10, 0.22,.

Example 38.Preparati0 n 0f 6-chl0r0-l7a-ethyl-3,8-hydroxypregna-4,6-dien-20-one To a solution of 200 mg. of6-ch1oro-l7a-ethylpregna- 4,6-dien-3,20-dione (Example 34) in 75 ml. ofmethanol, 5 ml. of tet-rahydrofuran and 1 ml. of water is added 200 mg.of sodium borohydride; the solution is kept at room temperature for 16hours. The solvents are removed, and the residue is distributed betweenmethylene chloride and a 1% sodium hydroxide solution. The organic layeris washed with saline, dried over magnesium sulfate and evaporated. Theresidue crystallizes from acetone-hexane to give white crystals, meltingpoint 192193 C.,

235, 242, 250 mp; x335; 2.85, 5.02,.

Example 39.Preparati0n of 6-chl0r0-17a-0cryl-3B-hydroxypregna-4,6-dien-20-0ne XIVIcOH max.

Treatment of 6-chloro-17a-octylpregna-4,6-diene-3,20- dione (Example 37)with sodium borohydride in the manner described in Example 38 produces6-ChlO'f0-17ozoctyl-3fl-hydroxypregna-4, 6-diene-20one.

E 2 Example 40.Preparati0n of 3,8-acet0xy-6-chl0ro- 1 7 a-ethylpregna-4,6-dien-20-0ne Treatment of 6-chloro-17a-ethylSB-hydroxy-pregna- 4,6-dien-20-one (Example 38) with acetic anhydride inpyridine as described in Example 19 is productive of 3,9-acetoxy-6-chloro-17a-ethylpregna-4,6-dien-20-one.

Example 41.Preparati0n of 3 B-acet0xy-6-chl0r0- I 7 a-octylpregna-4,6-dien-20-0ne Treatment of 6-chloro-17a-oetyl 3B-hydroxypregna-4,6-dien-20-one (Example 39) with acetic anhydride by the procedure ofExample 19 produces 3fi-acetoxy-6-chloro-17a-octylpregna-4,6-dien-20-one.

Example 42."reparati0n of I7a-ethylpregn-S-en-ZO-one To a solution of360 mg. of 3,8-chloro-17a-ethylpregn- 5-en-20-one (Example 7) in 15 ml.of boiling amyl alcohol are added small pieces of sodium metal. Eachaddition is made after all metal has dissolved and a total of 2 g. ofmetal is added. The amyl alcohol is removed, and the residue isdistributed between water and methylene chloride. The solvent is removedfrom the organic layer and the residue is dissolved in 5 ml. ofpyridine. This solution is added to an ice-chilled slurry of 300 mg. ofchromium trioxide in pyridine. The mixture is kept at room temperaturefor 16 hours and then poured into water. The product is isolated withethyl acetate to give material which has and no appreciable absorptionat 207/1111. in the ultraviolet region.

We claim.

1. The compound 17a-ethyl-35-fluoro 6-methylpregn- 5-en-20-one.

2. A 17-lower alkyl pregn-5-en-20-one of the formula:

wherein R is lower alkyl.

References Cited Bowers et a1.: J.A.C.S., 84, p. 1050-53 (1962).

Djerassi et aL: J. Org. Chem. 16, p. 754-60 (1951).

Gut: J. Org. Chem. 21, p. 1327-28 (1956) Kupfer: Tetrahedron 15, p.193-196 (1961).

Lowenthal: Tetrahedron, vol. 6, No. 4, p. 269303, June 1959.

Romo et al.: J.A.C.S. 73, p. 152833 (1951.).

Weiss et al.: Chem. and Industry, p. 118-119, January 1963 LEW-IS GOTTS,Primary Examiner.

H. FRENCH, J. R. GENTRY, Assistant Examiners.

1. THE COMPOUND 17-A-ETHYL-3B-FLUORO - 6-METHYLPREGN5-EN-20-ONE.